Carboxamide derivative and its diastereomers in stable crystalline form

ABSTRACT

The present disclosure relates to solid crystalline forms of N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) and the diastereomers thereof, and to methods for preparing such crystalline forms. Compound (I) and the diastereomers thereof are potent androgen receptor (AR) modulators useful as a medicament.

This is a continuation of application Ser. No. 15/997,040, filed Jun. 4,2018, which is a continuation of prior application Ser. No. 15/547,193,filed Jul. 28, 2017, and issued Jul. 3, 2018, as U.S. Pat. No.10,010,530, which was a national stage application under 35 U.S.C. § 371of International Application No. PCT/FI2016/050054, filed Jan. 28, 2016,which claims the benefit of priority of Finnish Patent Application No.20150033, filed Jan. 30, 2015, all of which are incorporated herein byreference.

FIELD OF THE INVENTION

The present disclosure relates to solid crystalline forms of thepharmaceutical compoundN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide(I) and the diastereomers thereof, and to methods for preparing suchcrystalline forms.

BACKGROUND OF THE INVENTION

The compoundN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide(1) and manufacture thereof have been disclosed in WO 2011/051540.Compound (I) is a potent androgen receptor (AR) modulator useful in thetreatment of cancer, particularly AR dependent cancer such as prostatecancer, and other diseases where AR antagonism is desired. Compound (I)is represented by the structure:

As the hydrogen atom of the pyrazole ring may exist in tautomericequilibrium between the 1- and 2-position, it is recognized by theskilled person that the above structure and the chemical name“N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide(I),” as referred to herein, is inclusive of the tautomer of compound(I), namelyN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide.

In addition to the chiral carbon atom shown in the chemical structureabove, compound (I) has another chiral carbon atom with hydroxy groupattached therein.

Therefore, compound (I) has two diastereomers, namelyN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((S)-1-hydroxyethyl)-1H-pyrazole-3-carboxamide(Ia)

andN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((R)-1-hydroxyethyl)-1H-pyrazole-3-carboxamide(Ib).

Due to the tautomeric equilibrium of the hydrogen atom between the 1-and 2-position in the pyrazole ring, the chemical name of diastereomers(Ia) and (Ib) are inclusive of the tautomers of (Ia) and (Ib), similarlyto compound (I) as explained above.

Compounds (Ia) and (Ib) are also potent androgen receptor (AR)modulators useful in the treatment of cancer, particularly AR dependentcancer such as prostate cancer, and other diseases where AR antagonismis desired.

SUMMARY OF THE INVENTION

It has now been found that compound (I) and its diastereomers (Ia) and(Ib) can be obtained in a stable and substantially pure crystalline formby crystallization under certain conditions.

Thus, the present disclosure provides, as one aspect,N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide(I) in crystalline form I.

In another aspect, the present disclosure provides diastereomerN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((S)-1-hydroxyethyl)-H-pyrazole-3-carboxamide(Ia) in crystalline form I′.

In yet another aspect, the present disclosure provides diastereomerN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((R)-1-hydroxyethyl)-1H-pyrazole-3-carboxamide(Ib) in crystalline form I″.

In yet another aspect, the present disclosure providesN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide(I) in crystalline form I as defined herein, substantially free of anyother crystalline form of compound (I).

In yet another aspect, the present disclosure provides diastereomerN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((S)-1-hydroxyethyl)-1H-pyrazole-3-carboxamide(Ia) in crystalline form I′ as defined herein, substantially free of anyother crystalline form of compound (Ia).

In yet another aspect, the present disclosure provides diastereomerN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((R)-1-hydroxyethyl)-1H-pyrazole-3-carboxamide(Ib) in crystalline form I″ as defined herein, substantially free of anyother crystalline form of compound (Ib).

The crystalline forms I, I′ and I″ are stable during pharmaceuticalprocessing and storage, and are therefore particularly suitable in thepreparation of pharmaceutical formulations.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the X-ray powder diffraction pattern of the crystallineform I of compound (I) obtained in Example 1.

FIG. 2 shows the X-ray powder diffraction pattern of the crystallineform I′ of compound (Ia) obtained in Example 4.

FIG. 3 shows the X-ray powder diffraction pattern of the crystallineform I″ of compound (Ib) obtained in Example 7.

DETAILED DESCRIPTION OF THE INVENTION

Crystalline form I of compound (1), crystalline form I′ of compound (Ia)and crystalline form I″ of compound (Ib) have been characterized byX-ray powder diffraction (XRPD) studies.

Accordingly, in one aspect, the present disclosure provides crystallineform I ofN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxy-ethyl)-1H-pyrazole-3-carboxamide(1) having an X-ray powder diffraction pattern comprising characteristicpeaks at about 8.5, 10.4, 16.6, 16.9, and 24.3 degrees 2-theta.

In another aspect, the present disclosure provides crystalline form I′ofN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((S)-1-hydroxyethyl)-1H-pyrazole-3-carboxamide(Ia) having an X-ray powder diffraction pattern comprisingcharacteristic peaks at about 9.3, 15.7, 17.0, 24.1 and 25.1 degrees2-theta.

In yet another aspect, the present disclosure provides crystalline formI″ ofN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((R)-1-hydroxyethyl)-1H-pyrazole-3-carboxamide(Ib) having an X-ray powder diffraction pattern comprisingcharacteristic peaks at about 9.2, 10.9, 15.1, 15.8 and 22.1 degrees2-theta.

In yet another aspect, the present disclosure provides crystalline formI ofN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide(1) having an X-ray powder diffraction pattern comprising characteristicpeaks at about 6.4, 8.5, 9.6, 9.7, 10.4, 12.8, 13.6, 14.9, 15.9, 16.6,16.9, 18.7, 19.2, 21.8, 24.3, and 25.5 degrees 2-theta.

In yet another aspect, the present disclosure provides crystalline formI′ ofN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((S)-1-hydroxyethyl)-1H-pyrazole-3-carboxamide(Ia) having an X-ray powder diffraction pattern comprisingcharacteristic peaks at about 9.3, 11.4, 11.5, 13.6, 14.7, 14.9, 15.7,16.1, 17.0, 17.7, 18.5, 19.1, 20.5, 21.5, 22.1, 22.6, 23.2, 23.6, 24.1,25.1, 26.2 and 27.2 degrees 2-theta.

In yet another aspect, the present disclosure provides crystalline formI″ ofN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((R)-1-hydroxyethyl)-1H-pyrazole-3-carboxamide(Ib) having an X-ray powder diffraction pattern comprisingcharacteristic peaks at about 7.9, 9.2, 10.9, 13.2, 14.8, 15.1, 15.5,15.8, 16.9, 18.4, 20.2, 20.5, 21.8, 22.1 and 24.3 degrees 2-theta.

In still another aspect, the present disclosure provides crystallineform I ofN—((S)-1-(3-(3-chloro-4-cyanophenyl)-H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide(1) characterized in that it provides an X-ray powder diffractionpattern substantially as illustrated in FIG. 1.

According to still another aspect, the present disclosure providescrystalline form I′ ofN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((S)-1-hydroxyethyl)-1H-pyrazole-3-carboxamide(Ia) characterized in that it provides an X-ray powder diffractionpattern substantially as illustrated in FIG. 2.

According to still another aspect, the present disclosure providescrystalline form I″ ofN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((R)-1-hydroxyethyl)-1H-pyrazole-3-carboxamide(Ib) characterized in that it provides an X-ray powder diffractionpattern substantially as illustrated in FIG. 3.

It is recognized by the skilled person that the X-ray powder diffractionpattern peak positions referred to herein can be subject to variationsof +/−0.15 degrees 2-theta according to various factors such astemperature, concentration, and instrumentation used. Therefore, signalsand peak positions are referred to herein as being at “about” specificvalues.

According to still another aspect, the present disclosure provides aprocess for preparing crystalline form I, I′ or I″ ofN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I),N—((S)-1-(3-(3-chloro-4-cyanophenyl)-H-pyrazol-1-yl)propan-2-yl)-5-((S)-1-hydroxyethyl)-1H-pyrazole-3-carboxamide(Ia) orN—((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((R)-1-hydroxyethyl)-1H-pyrazole-3-carboxamide(Ib), respectively, comprising

a) mixing N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I),N—((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((S)-1-hydroxyethyl)-1H-pyrazole-3-carboxamide(Ia) orN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((R)-1-hydroxyethyl)-1H-pyrazole-3-carboxamide(Ib) with a mixture of acetonitrile and water;

b) heating the mixture from step a) to form a solution;

c) cooling the solution from step b) to about 0-50° C.; and

d) isolating the crystalline form.

In still another aspect, the present disclosure provides a process forthe manufacture of diastereomer (Ia) or (Ib) comprising

a) reducing compound of formula (1)

wherein R is H or C₁₋₆ alkyl, with a ketoreductase enzyme to obtaincompound of formula (2) in optically active form, wherein R is asdefined above;

b) optionally protecting the hydroxyl group of compound of formula (2);

c) in case R is an C₁₋₆ alkyl, subjecting the compound of formula (2),wherein the hydroxyl group is optionally protected, to cleavage of theester bond to obtain compound (3);

wherein the hydroxyl group is optionally protected; and

d) treating compound (3), wherein the hydroxyl group is optionallyprotected, with(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile, and, incase the hydroxyl group is protected, deprotecting the hydroxyl group,to obtain compound (Ia) or (Ib).

Compound (1) can be synthesized using the procedures described in WO2011/051540.

Pure diastereomers (Ia) and (Ib) can be suitably synthesized, forexample, using ketoreductase enzymes (KREDs) for both S- and R-selectivereduction of compound 1 to compound 2 as shown in Scheme 1, wherein R isH or C₁₋₆ alkyl.

For example, Codexis KRED-130 and KRED-NADH-110 enzymes are useful forobtaining excellent stereoselectivity, even stereospecificity. In Scheme1 the starting material 1 is preferably an ester (R═C₁₋₆ alkyl), forexample ethyl ester (R=ethyl), such as to facilitate extraction of theproduct into the organic phase as the compound where R═H has a tendencyto remain in the water phase. Intermediate 2 can be protected,preferably with silyl derivatives such as tert-butyldiphenylsilyl, inorder to avoid esterification in amidation step. In the case of R═C₁₋₆alkyl, ester hydrolysis is typically performed before amidation step,preferably in the presence of LiOH, NaOH or KOH. Amidation from compound3 to compound 5 is suitably carried out using EDCI HBTU, DIPEA systembut using other typical amidation methods is also possible. Deprotectionof 5 give pure diastereomers (Ia) and (Ib).

Pyrazole ring without NH substitution is known tautomerizablefunctionality and is described here only as single tautomer but everyintermediate and end product here can exist in both tautomeric forms atthe same time.

The stereochemistry of the compounds can be confirmed by using opticallypure starting materials with known absolute configuration asdemonstrated in Scheme 2, wherein R═H or C₁₋₆ alkyl, preferably alkyl,for example ethyl. The end products of Scheme 2 are typically obtainedas a mixture of tautomers at +300K ¹H-NMR analyses in DMSO.

The crystalline forms I, I′ and I″ of compounds (I), (Ia) and (Ib),respectively, can be prepared, for example, by dissolving the compoundin question in an acetonitrile:water mixture having volume ratio fromabout 85:15 to about 99:1, such as from about 90:10 to about 98:2, forexample about 95:5, under heating and slowly cooling the solution untilthe crystalline form precipitates from the solution. The concentrationof the compound in the acetonitrile:water solvent mixture is suitablyabout 1 kg of the compound in 5-25 liters of acetonitrile:water solventmixture, for example 1 kg of the compound in 10-20 liters ofacetonitrile:water solvent mixture. The compound is suitably dissolvedin the acetonitrile:water solvent mixture by heating the solution, forexample near to the reflux temperature, for example to about 60-80° C.,for example to about 75° C., under stirring and filtering if necessary.The solution is suitably then cooled to about 0-50° C., for example toabout 5-35° C., for example to about RT, over about 5 to about 24 hours,for example over about 6 to 12 hours, and stirred at this temperaturefor about 3 to 72 hours, for example for about 5 to 12 hours. Theobtained crystalline product can then be filtered, washed, and dried.The drying is suitably carried out in vacuum at about 40 to 60° C., forexample at 55° C., for about 1 to 24 hours, such as for about 2 to 12hours, for example 2 to 6 hours.

The crystalline forms I, I′ and I″ of compounds (I), (Ia) and (Ib),respectively, are useful as medicaments and can be formulated intopharmaceutical dosage forms, such as tablets and capsules for oraladministration, by mixing with pharmaceutical excipients known in theart.

The disclosure is further illustrated by the following examples.

Example 1. Crystallization ofN—((S)-1-(3-(3-Chloro-4-Cyanophenyl)-1H-Pyrazol-1-Yl)-Propan-2-Yl)-5-(l-Hydroxyethyl)-1H-Pyrazole-3-Carboxamide(I)

N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxy-ethyl)-1H-pyrazole-3-carboxamide(I) (5 g), 71.25 ml of acetonitrile, and 3.75 ml of distilled water werecharged to a flask, and the mixture was heated up to 75° C. The mixturewas slowly cooled down to RT and stirred at RT for 3 days. The solidobtained was filtered and washed twice with acetonitrile:water (9.5ml:0.5 ml). The product was dried under vacuum at 40° C. and finally at60° C. to obtain 4.42 g of crystalline title compound (yield of 88%)which was used in X-ray diffraction study.

Example 2. X-Ray Diffraction Study of Crystalline Compound (I)

The crystalline form of compound (1) obtained in Example 1 was analysedby X-ray powder diffraction method. The measurements were performed withthe X-ray powder diffractometer PANalytical X'Pert PRO at roomtemperature using Cu filled X-ray tube (45 kV×40 mA) as the X-raysource, a fixed 1 anti-scatter slit, a programmable divergence slit with5.0 mm irradiated length and the real time multiple strip detectorX'Celerator. Data collection was done in 0.008° steps at a scan speed of1°/min in the range of 3−80° 2θ. The crystalline form was characterizedby an X-ray powder diffraction pattern as shown in FIG. 1 and exhibitingcharacteristic peaks at about the following 2-theta values:

Angle 2-theta ° 6.4 8.5 9.6 9.7 10.4 12.8 13.6 14.9 15.9 16.6 16.9 18.719.2 21.8 24.3 25.5

Example 3. Synthesis ofN—((S)-1-(3-(3-Chloro-4-Cyanophenyl)-1H-Pyrazol-1-Yl)-Propan-2-Yl)-5-((S)-1-Hydroxyethyl)-1H-Pyrazole-3-Carboxamide(Ia) a) Ethyl-5-((S)-1-hydroxyethyl)-1H-pyrazole-3-carboxylate

MgSO₄×7H₂O (341 mg), NADP monosodium salt (596 mg), D(+)-glucose (9.26g) and optimized enzyme CDX-901 lyophilized powder (142 mg) were addedto 0.2 mM of KH₂PO₄ buffer (pH 7.0, 709 ml) to prepare solution I. Tothis solution I was added solution II which containedethyl-5-acetyl-1H-pyrazole-3-carboxylate (8.509 g; 46.70 mmol), EtOH (28ml) and KRED-130 (NADPH ketoreductase, 474 mg). The mixture was agitatedat 30-32° C. for 5.5 h (monitoring by HPLC) and allowed to cool to RT.The mixture was evaporated to smaller volume and the residue wasagitated with diatomaceous earth and filtered. The mother liquid wasextracted with 3×210 ml of EtOAc and dried. The solution was filteredthrough silica (83 g) and evaporated to dryness to give 7.40 g of thetitle compound. The optical purity was 100% ee.

b) Ethyl5-((S)-1-((Tert-Butyldiphenylsilyl)Oxy)Ethyl)-1H-Pyrazole-3-Carboxylate

Diphenyl-tert-butyl chlorosilane (7.48 g, 27.21 mmol) was added in 26 mlof DMF to a mixture of compound of Example 3(a) (5.00 g, 27.15 mmol) andimidazole (2.81 g, 41.27 mmol) in DMF (50 ml) at RT. The mixture wasstirred at RT for 24 h. Saturated aqueous NaHCO₃ (56 ml) and water (56ml) were added and the mixture was stirred at RT for 20 min. The mixturewas extracted with 2×100 ml of EtOAc. Combined organic phases werewashed with water (1×100 ml, 1×50 ml), dried (Na₂SO₄), filtered andconcentrated to give 10.92 g of crude title compound.

c)5-((S)-1-((Tert-Butyldiphenylsilyl)Oxy)Ethyl)-1H-Pyrazole-3-CarboxylicAcid

2 M NaOH (aq) (38.8 ml; 77.5 mmol) was added to a solution of thecompound of Example 3(b) (10.9 g, 25.8 mmol) in 66 ml of THF. Themixture was heated up to reflux temperature. Heating was continued for2.5 h and THF was removed in vacuum. Water (40 ml) and EtOAc (110 ml)were added. Clear solution was obtained after addition of more water (10ml). Layers were separated and aqueous phase was extracted with 100 mlof EtOAc. Combined organic phases were dried (Na₂SO₄), filtered andconcentrated to give 9.8 g of the title compound.

d)5-((S)-1-((Tert-Butyldiphenylsilyl)Oxy)Ethyl)-N—((S)-1-(3-(3-Chloro-4-Cyano-Phenyl)-H-Pyrazol-1-Yl)Propan-2-Yl)-1H-Pyrazole-3-Carboxamide

Under nitrogen atmosphere HBTU (0.84 g; 2.22 mmol), EDCI×HCl (3.26 g;17.02 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (3.86 g;14.80 mmol) were added to a mixture of crude compound of Example 3(c)(8.68 g; purity 77.4 area-%) and DIPEA (2.20 g; 17.02 mmol) in DCM (50ml). The mixture was stirred at RT for 46 h (6 ml of DCM was added after20 h). The mixture was washed with 3×20 ml of water, dried (Na₂SO₄),filtered and concentrated to give 13.7 g of crude title compound.

e)N—((S)-1-(3-(3-Chloro-4-Cyanophenyl)-1H-Pyrazol-1-Yl)Propan-2-Yl)-5-((S)-1-Hydroxyethyl)-1H-Pyrazole-3-Carboxamide(Ia)

TBAF hydrate (Bu₄NF×3H₂O; 2.34 g; 7.40 mmol) in 10 ml of THF was addedto the solution of the compound of Example 3(d) (9.43 g; 14.79 mmol) inTHF (94 ml) at 0° C. under nitrogen atmosphere. Stirring was continuedat RT for 21.5 h and the mixture was concentrated. DCM (94 ml) was addedto the residue and the solution was washed with 3×50 ml of water, dried(Na₂SO₄), filtered and concentrated. Crude product was purified by flashchromatography (EtOAc/n-heptane) to give 2.1 g of the title compound.¹H-NMR (400 MHz; d6-DMSO; 300K): Major tautomer (˜85%): δ 1.11 (d, 3H),1.39 (d, 3H), 4.24-4.40 (m, 2H), 4.40-4.50 (m, 1H), 6.41 (s, 1H), 6.93(d, 1H), 7.77-7.82 (m, 1H), 7.88-8.01 (m, 2H), 8.08 (s, 1H), 8.19 (d,1H), 13.02 (broad s, 1H). Minor tautomer (˜15%) δ 1.07-1.19 (m, 3H),1.32-1.41 (m, 3H), 4.24-4.40 (m, 2H), 4.40-4.50 (m, 1H), 6.80 (broad s,1H), 6.91-6-94 (m, 1H), 7.77-7.82 (m, 1H), 7.88-8.01 (m, 2H), 8.05-8.09(m, 1H), 8.31 (d, 1H), 13.10 (broad s, 1H).

Example 4. Crystallization ofN—((S)-1-(3-(3-Chloro-4-Cyanophenyl)-1H-Pyrazol-1-Yl)Propan-2-Yl)-5-((S)-1-Hydroxyethyl)-1H-Pyrazole-3-Carboxamide(Ia)

N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((S)-1-hydroxyethyl)-1H-pyrazole-3-carboxamide(Ia) (5.00 g; 12.54 mmol) was mixed with 47.5 ml of ACN and 2.5 ml ofwater. The mixture was heated until compound (Ia) was fully dissolved.The solution was allowed to cool slowly to RT to form a precipitate. Themixture was then further cooled to 0° C. and kept in this temperaturefor 30 min. The mixture was filtered and the precipitate was dried undervacuum to obtain 4.50 g of crystalline title compound which was used inthe X-ray diffraction study.

Example 5. X-Ray Diffraction Study of Crystalline Compound (Ia)

The crystalline form of compound (Ia) obtained in Example 4 was analysedby X-ray powder diffraction method as described in Example 2. Thecrystalline form was characterized by an X-ray powder diffractionpattern as shown in FIG. 2 and exhibiting characteristic peaks at aboutthe following 2-theta values:

Angle 2-theta ° 9.3 11.4 11.5 13.6 14.7 14.9 15.7 16.1 17.0 17.7 18.519.1 20.5 21.5 22.1 22.6 23.2 23.6 24.1 25.1 26.2 27.2

Example 6. Synthesis ofN—((S)-1-(3-(3-Chloro-4-Cyanophenyl)-1H-Pyrazol-1-Yl)-Propan-2-Yl)-5-((R)-1-Hydroxyethyl)-1H-Pyrazole-3-Carboxamide(Ib) a) Ethyl-5-((R)-1-hydroxyethyl)-1H-pyrazole-3-carboxylate

Potassium dihydrogen phosphate buffer (Solution I) was prepared bydissolving potassium dihydrogen phosphate (11.350 g, 54.89 mmol) towater (333 mil) and adjusting pH of the solution to 7.0 by addition of 5M solution of NaOH. MgSO₄×7 H₂O (1.650 g), NAD monosodium salt (0.500g), D(+)-glucose (10.880 g) and optimised enzyme CDX-901 lyophilisedpowder (0.200 g) were added to Solution I. To this solution (SolutionII) were added KRED-NADH-110 (0.467 g),ethyl-5-acetyl-1H-pyrazole-3-carboxylate (10.00 g; 54.89 mmol) and2-methyltetrahydro-furan (16 ml). The mixture was agitated at 30° C. for11 h and allowed to cool to RT overnight. The pH of the mixture was keptat 7 by addition of 5 M solution of NaOH. The mixture was evaporated toa smaller volume. The evaporation residue was agitated for 10 min withdiatomaceous earth (40 g) and activated charcoal (0.54 g), and filtered.Material on the filter was washed with water (40 ml) and the washingswere combined with the filtrate. Layers were separated and aqueous phasewas extracted with EtOAc (450 ml and 2×270 ml). Combined organic phaseswere dried over Na₂SO₄, filtered and evaporated to dryness to give 9.85g of the title compound (100% ee).

b)Ethyl-5-((R)-1-((Tert-Butyldiphenylsilyl)Oxy)Ethyl)-1H-Pyrazole-3-Carboxylate

Imidazole (5.32 g; 78.08 mmol) was added to a DCM (67 ml) solution ofthe compound of Example 6(a) (9.85 g; 53.48). The mixture was stirreduntil all reagent was dissolved and tert-butyldiphenyl chlorosilane(13.21 ml; 50.80 mmol) was added to the mixture. The mixture was stirredfor 1.5 h, 70 ml of water was added and stirring was continued for 15min. Layers were separated and organic phase was washed with 2×70 ml ofwater and dried over Na₂SO₄, filtered and concentrated to give 22.07 gof crude title compound.

c)5-((R)-1-((Tert-Butyldiphenylsilyl)Oxy)Ethyl)-1H-Pyrazole-3-CarboxylicAcid

Compound of Example 6(b) (11.3 g; 26.74 mmol; theoretical yield from theprevious step) was dissolved in 34 ml of THF and 50 ml of 2 M NaOH (aq.)was added. The mixture was heated under reflux temperature for 70 min.The mixture was extracted with 2×55 ml of EtOAc and combined organicphases were washed with brine, dried over Na₂SO₄, filtered andconcentrated. Evaporation residue was triturated in 250 ml of n-heptane,filtered and dried to give 17.58 g of crude title compound.

d)5-((R)-1-((Tert-Butyldiphenylsilyl)Oxy)Ethyl)-N—((S)-1-(3-(3-Chloro-4-Cyano-Phenyl)-1H-Pyrazol-1-Yl)Propan-2-Yl)-1H-Pyrazole-3-Carboxamide

A mixture of the compound of Example 6(c) (11.14 g; 26.75 mmol;theoretical yield from the previous step), 91 ml of DCM, HBTU (1.52 g;4.01 mmol), EDCI×HCl (5.90 g; 30.76 mmol),(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (6.97 g;26.75 mmol) and DIPEA (3.98 g; 30.76 mmol) was stirred at RT for 3 h andat 30° C. for 22 h. The mixture was washed with 2×90 ml of 0.5 M HCl and4×90 ml of water, dried over Na₂SO₄, filtered and concentrated. Crudeproduct was purified by flash column chromatography (n-heptane-EtOAc) togive 16.97 g of title compound.

e)N—((S)-1-(3-(3-Chloro-4-Cyanophenyl)-1H-Pyrazol-1-Yl)Propan-2-Yl)-5-((R)-1-Hydroxyethyl)-1H-Pyrazole-3-Carboxamide(Ib)

A mixture of the compound of Example 6(d) (6.09 g; 9.56 mmol), 61 ml ofTHF and TBAF was stirred at 40° C. for 6.5 h. The mixture wasconcentrated and 61 ml of EtOAc was added to the evaporation residue.Solution was washed with 2×50 ml of 0.5 M HCl and 4×50 ml of water,dried over Na₂SO₄, filtered and concentrated. Crude product was purifiedby flash column chromatography (n-heptane-EtOAc) to give 1.71 g of thetitle compound. ¹H-NMR (400 MHz; d6-DMSO; 300K): Major tautomer (˜85%):δ 1.10 (d, 3H), 1.38 (d, 3H), 4.14-4.57 (m, 2H), 5.42 (d, 1H), 6.39 (s,1H), 6.86-6.98 (m, 1H), 7.74-7.84 (m, 1H), 7.86-8.02 (m, 2H), 8.08 (s,1H), 8.21 (d, 1H), 13.04 (broad s, 1H). Minor tautomer (˜15%) δ0.95-1.24 (m, 3H), 1.25-1.50 (m, 3H), 4.14-4.57 (m, 2H), 4.60-4.90 (m,1H), 5.08 (d, 1H), 6.78 (broad s, 1H), 6.86-6.98 (m, 1H), 7.77-7.84 (m,1H), 7.86-8.02 (m, 2H), 8.02-8.12 (m, 1H), 8.32 (d, 1H), 13.11 (broad s,1H).

Example 7. Crystallization ofN—((S)-1-(3-(3-Chloro-4-Cyanophenyl)-1H-Pyrazol-1-Yl)Propan-2-Yl)-5-((R)-1-Hydroxyethyl)-1H-Pyrazole-3-Carboxamide(Ib)

N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((R)-1-hydroxyethyl)-1H-pyrazole-3-carboxamide(Ib) (3.7 g; 9.28 mmol) was mixed with 70 ml of ACN and 3.5 ml of water.The mixture was heated to reflux temperature until compound (Ib) wasfully dissolved. The solution was allowed to cool slowly. The mixturewas filtered at 50° C. to obtain 6.3 mg of the precipitate. Motherliquid was cooled to 41° C. and filtered again to obtain 20.7 mg of theprecipitate. Obtained mother liquid was then cooled to 36° C. andfiltered to obtain 173 mg of the precipitate. The final mother liquidwas cooled to RT, stirred overnight, cooled to 0° C., filtered, washedwith cold ACN:water (1:1) and dried to obtain 2.71 g of the precipitate.The precipitates were checked for optical purity and the lastprecipitate of crystalline title compound (optical purity 100%) was usedin the X-ray diffraction study.

Example 8. X-Ray Diffraction Study of Crystalline Compound (Ib)

The crystalline form of compound (Ib) obtained in Example 7 was analysedby X-ray powder diffraction method as described in Example 2. Thecrystalline form was characterized by an X-ray powder diffractionpattern as shown in FIG. 3 and exhibiting characteristic peaks at aboutthe following 2-theta values:

Angle 2-theta ° 7.9 9.2 10.9 13.2 14.8 15.1 15.5 15.8 16.9 18.4 20.220.5 21.8 22.1 24.3

Example 9. Synthesis of Ethyl-5-((S)1-Hydroxyethyl)-1H-Pyrazole-3-Carboxylate

Zinc trifluoromethanesulfonate (0.259 g; 0.713 mmol) and(S)-(−)-3-butyn-2-ol (0.25 g; 3.57 mmol) were added to 0.75 ml (5.35mmol) of Et₃N under nitrogen atmosphere. Ethyldiazoacetate (0.45 ml;4.28 mmol) was added slowly and the mixture was heated at 100° C. for 2h. The mixture was cooled to RT and 5 ml of water was added. The mixturewas washed with 15 ml of DCM, 5 ml of water was added and phases wereseparated. Water phase was washed twice with DCM, all organic layerswere combined, dried with phase separator filtration and evaporated todryness to give 0.523 g of crude material. The product was purified bynormal phase column chromatography (0-5% MeOH:DCM) to give 0.165 mg ofthe title compound. ¹H-NMR (400 MHz; d6-DMSO; temp+300 K): Tautomer 1(major 77%): δ 1.28 (t, 3H), 1.39 (d, 3H), 4.20-4.28 (m, 2H), (d, 1H),4.75-4.85 (m, 1H) 5.43 (broad d, 1H), 6.54 (broad s, 1H), 13.28 (broads, 1H). Tautomer 2 (minor 23%): δ 1.28 (t, 3H), 1.39 (d, 3H), 4.20-4.28(m, 2H), 4.66-4.85 (m, 1H), 5.04-5.15 (broad s, 1H), 6.71 (broad s, 1H),13.60 (broad s, 1H).

Example 10. Ethyl-5-((R)-1-Hydroxyethyl)-1H-Pyrazole-3-Carboxylate

Zinc trifluoromethanesulfonate (1.037 g; 2.85 mmol) and(R)-(+)-3-butyn-2-ol (1.00 g; 14.27 mmol) were added to 2.98 ml (21.40mmol) of Et₃N under nitrogen atmosphere. Ethyldiazoacetate (1.80 ml;21.40 mmol) was added slowly and then refluxed for 3 h. The mixture wascooled to RT and 45 ml of water was added. The mixture was extractedwith 3×50 ml of DCM, organic layers were combined, dried with phaseseparator filtration and evaporated to dryness to give 2.503 g of crudematerial which was purified by normal phase column chromatography (0-10%MeOH:DCM) to give 0.671 mg of the title compound. ¹H-NMR (400 MHz:d6-DMSO; temp+300 K): Tautomer 1 (major 78%): δ 1.28 (t, 3H), 1.39 (d,3H), 4.18-4.35 (m, 2H), (d, 1H), 4.75-4.85 (m, 1H) 5.42 (broad d, 1H),6.54 (s, 1H), 13.29 (broad s, 1H). Tautomer 2 (minor 22%): δ 1.28 (t,3H), 1.39 (d, 3H), 4.18-4.35 (m, 2H), 4.66-4.85 (m, 1H), 5.09 (broad s,1H), 6.71 (broad s, 1H), 13.61 (broad s, 1H).

Abbreviations

ACN: acetonitrile

DCM: dichloromethane

DIPEA: N,N-diisopropyl-ethyl amine

DMF: dimethylformamide

DMSO: dimethylsulfoxide

EDCI×HCl: N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride

EtOAc: ethylacetate

EtOH: ethanol

HBTU: o-benzotriazole-N,N,N′,N′-tetramethyl-uroniumhexafluoro-phosphate

KRED: ketoreductase (enzyme)

RT: room temperature

TFA: trifluoroacetic acid

The invention claimed is:
 1. A pharmaceutical dosage form in the form ofa tablet or a capsule for oral administration comprising crystallineform I of N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) having anX-ray powder diffraction pattern comprising characteristic peaks atabout 8.5, 10.4, 16.6, 16.9, and 24.3 degrees 2-theta, together with apharmaceutical excipient.
 2. The pharmaceutical dosage form according toclaim 1, wherein the crystalline form I ofN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) furtherhas an X-ray powder diffraction pattern comprising characteristic peaksat about 9.7, 15.9, 19.2, 21.8, and 25.5 degrees 2-theta.
 3. A methodfor the treatment of prostate cancer comprising administering to asubject in need thereof a therapeutically effective amount of apharmaceutical dosage form according to claim 1 or 2.